The development of several highly lipophilic potential antineoplastic agents will be continued with the purpose of probing neoplasia of the CNS. The intent is to relate cytotoxicity and antitumor activity to the physicochemical properties of the agents in order to better define the requirements for therapeutic access to the CNS. Specifically, information is being sought regarding the characteristics of three related series of compounds I-3, including physicochemical information such as rates of hydrolysis and alkylation in situ, lipophilicity, and the nature of the transition state. Physicochemical (derivatives of azotricyclo-undecane) correlations will be drawn within and between each series to establish a profile of each molecular system. Concomitantly, the biological and antitumor profile for each system will be determined utilizing an integrated approach consisting of in vivo kinetic profiles of drug entry into the cerebrospinal fluid and brains of rabbits. The detection and determination of the existence of passive diffusion and/or carrier-mediated transport, and the measurement of the effectiveness of subcellular localization in the CNS will also be accomplished. Antitumor screening will be carried out in in vitro KB-9 human nasocarcinoma cells, and samples will be submitted to NCI for in vivo screening. Using these data, correlations will be drawn which should afford new insights into the physicochemical requirements for CNS-active antitumor agents.